1. Field of the Invention
This invention relates to pyrrolo[1,2-a]pyrroles, and especially to the synthesis of (.+-.)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid and related compounds.
2. Background of the Invention
5-Aroyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids, also known as 5-aroyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acids, of formula I, and the ##STR2## pharmacologically acceptable salts and esters thereof, are useful as analgesic, anti-inflammatory, and anti-pyretic agents for mammals, including man. They are also smooth muscle relaxants. Two exemplary compounds under clinical study in man are ketorolac, 5-benzoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, (I, Ar=C.sub.6 H.sub.5), and anirolac, 5-p-anisoyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, (I, Ar=p-CH.sub.3 O-C.sub.6 H.sub.5), both disclosed in U.S. Pat. No. 4.089,969 to Muchowski et al. Other compounds, where the 5-aroyl substituents are substituted or unsubstituted benzoyl, furoyl, thenoyl, and pyrroyl, and where the 6-position on the pyrrolo-pyrrole nucleus is optionally substituted by lower alkyl or halogen, and the uses thereof, are also disclosed in a series of patents assigned to Syntex (U.S.A.) Inc., beginning with U.S. Pat. No. 4,089,969, and including U.S. Pat. Nos. 4,087,539; 4,097,579; 4,140,698; 4,232,038; 4,344,943; 4,347,186; 4,458,081; 4,347,187; 4,454,326; 4,347,185; 4,505,927; 4,456,759; 4,353,829; 4,397,862; 4,457,941; and 4,454,151. U.S. Pat. Nos. 4,511,724 and 4,536,512, assigned to Merck & Co., Inc., disclose 5-(substituted pyrrol-2-oyl)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives and 5-(2,3-dihydro-1H-pyrrolo[1,2-a]pyrrol-2-oyl)-2,3-dihydro-1H-pyrrolo[1,2-a ]pyrrole-1-carboxylic acid derivatives, respectively; while U.S. Pat. No. 4,533,671, also assigned to Merck & Co., Inc., discloses 5-(2,3-dihydro-1H-pyrrolo[1,2-a]pyrrol-2-oyl)-2-pyrrolealkanoic acids and analogs.
Various methods for the preparation of these pyrrolo-pyrroles are exemplified in the patent and chemical literature, and many proceed through a common intermediate, 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, (II), or its alkyl ester; ##STR3##
The alkyl ester may be readily 5-aroylated by methods such as those described in the previously-cited patents and in U.S. Pat. No. 4,496,741 to Doherty, and saponified, to yield a 5-aroyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (I).
Several methods of preparation of compound (II) are known in the patent and chemical literature, with most proceeding through 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid, which is selectively decarboxylated, by methods also described in the literature, to the 1-carboxylic acid.
Syntheses not involving the 1,7-dicarboxylate include those set forth in, for example, U.S. Pat. Nos. 4,140,698 and 4,344,943, referred to previously. These syntheses involve the preparation of 1-(2-iodoethyl)-pyrrole-2-acetonitrile (III, Z=CN) or an alkyl 1-(2-iodoethyl)-pyrrole-2-acetate (III, Z=COOR) and coupling to form the saturated ring, giving compound (IV). ##STR4##
U.S. Pat. No. 4,347,186 discloses a synthesis of (I) by the cyclization of a 1-[3,3-di(alkoxycarbonyl)-propyl]-2-methanesulfonyl-5-aroylpyrrole (V) to the 1,1-dicarboxylate (VI), followed by hydrolysis to the 1-carboxylate. ##STR5##
Commonly assigned U.S. patent application Ser. No. 06/868,835, filed May 19, 1986, discloses a similar synthesis in which a 1-[3,3-di(alkoxycarbonyl)propyl]-2-halo-5-aroylpyrrole is converted to the 1,1-dicarboxylate (VI), followed by hydrolysis to the 1-carboxylate.
In each of these patents, the saturated ring is formed wholly or partially by the N-substituent on the pyrrole.
Pizzorno et al., in J. Org. Chem., v.39, p.731 (1974), disclose the cycloaddition of ethyl propiolate to N-formyl-L-proline (VII) to yield ethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrroly-7-carboxylate (VIII), which is subsequently reduced to the corresponding pyrrolizidine carboxylate. ##STR6##
British Pat. No. 1,234,139 discloses compounds including 7-hydroxymethyl- and 7-formyl-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole, prepared from the alkaloid derivative supinidine.
The disclosures of these patents and articles, and other patents and articles referred to throughout this specification, are incorporated herein by reference.